Tolvaptan (OPC-41061) is a highly potent selective, competitive vasopressin V2-receptor antagonist with Ki of 0.43 nM, >200-fold more selective than for V1A-receptors; inhibits cAMP production induced by AVP with no intrinsic agonist activity; clearly produces dose-dependent aquaresis in rats; orally active.(In Vitro):Tolvaptan (0-100 μM; 24-168 h) decreases the growth of HepG2 cells.Tolvaptan (20-100 μM; 24-48 h) induces cell death in HepG2 cells.Tolvaptan (0-100 μM; 24-48 h) affects cell cycle of HepG2 cells.Tolvaptan (0-100 μM; 24-48 h) causes DNA damage and induces apoptosis of HepG2 cells.Tolvaptan (0-100 μM; 24-48 h) decreases cyclins and CDKs, and increases γ-H2AX, PARP cleavage and LC3B-II in HepG2 cells.Tolvaptan (0-100 μM; 4-24 h) induces phosphorylation of JNK, ERK1/2 and p38 in HepG2 cells.Tolvaptan (0-100 μM; 24-28 h) induces autophagy of HepG2 cells.(In Vivo):Tolvaptan (10 mg/kg; p.o. once per day for 22 days) improves cyclophosphamide (CP)-induced nephrotoxicity in rats.
Tolvaptan (10 mg/kg; p.o. once per day for 22 days) improves cyclophosphamide (CP)-induced nephrotoxicity in rats. Animal model: Male albino rats with cyclophosphamide intraperitoneal injection. Dosage: 10 mg/kg. Administration: Oral gavage; 10 mg/kg once per day; for 22 days. Result: Improved the level of urine volume, serum Na+, serum osmolarity, urinary creatinine, free water clearance, serum creatinine, urea, serum K+, blood pressure, urine osmolarity, fractional excretion of sodium and signs of nephrotoxicity in mice. Decreased caspase-3, Bax and pro-inflammatory cytokines, and increased antiapoptotic Bcl-2 in renal tissue of mice.
In Vitro
Tolvaptan (0-100 μM; 24-168 h) decreases the growth of HepG2 cells. Tolvaptan (20-100 μM; 24-48 h) induces cell death in HepG2 cells. Tolvaptan (0-100 μM; 24-48 h) affects cell cycle of HepG2 cells. Tolvaptan (0-100 μM; 24-48 h) causes DNA damage and induces apoptosis of HepG2 cells. Tolvaptan (0-100 μM; 24-48 h) decreases cyclins and CDKs, and increases γ-H2AX, PARP cleavage and LC3B-II in HepG2 cells. Tolvaptan (0-100 μM; 4-24 h) induces phosphorylation of JNK, ERK1/2 and p38 in HepG2 cells. Tolvaptan (0-100 μM; 24-28 h) induces autophagy of HepG2 cells. Cell Viability Assay Cell line: HepG2 cells. Concentration: 0-100 μM. Incubation time: 24, 48, 96 and 168 hours. Result: Time- and dose-dependently inhibited HepG2 cells with IC50s of >100, 52.2, 33.0 and 27.1 μM at 24, 48, 96 and 168 hours, respectively. Cell Viability Assay Cell line: HepG2 cells. Concentration: 20, 40, 60, 80, and 100 μM. Incubation time: 24 and 48 hours. Result: Time- and dose-dependently inhibited HepG2 cell growth and caused cell death, with LDH released at a concentration over 40 μM. Caused oxidative DNA damage and increased ROS production with a concentration of 60-100 μM. Cell Cycle Analysis Cell line: HepG2 cells. Concentration: 0-100 μM. Incubation time: 24 and 48 hours. Result: Caused cell cycle arrest at the G2 phase, dose-dependently increased the percentage of G0/G1 phase cells with a concentration of 20-60 μM and increased the percentage of G2/M phase cells with a concentration of 60-100 μM. Western blot analysis. Cell line: HepG2 cells. Concentration: 0-100 μM. Incubation time: 24 and 48 hours. Result: Dose-dependently decreased cyclin D1, cyclin D3, cyclin B1, CDK1, CDK2, CDK4, and CDK6, and increased γ-H2AX which is a maker of DNA double strand breaks in HepG2 cells. Increased the full length PARP into cleavage situation and induced PARP cleavage. Apoptosis Analysis Cell line: HepG2 cells. Concentration: 0-100 μM. Incubation time: 24 and 48 hours. Result: Induced cell apoptosis with increasing caspase 3/7 activity at a dose over 40 μM. Western blot analysis. Cell line: HepG2 cells. Concentration: 0-100 μM. Incubation time: 4 and 24 hours. Result: Induced the activation of ERK1/2 and p38 after 4 or 24 h of exposure at a concentration over 60 μM in HepG2 cells. Cell Autophagy Assay Cell line: HepG2 cells. Concentration: 0-100 μM. Incubation time: 24 and 48 hours. Result: Induced cell autophagy with autophagosome formation and an increasing lysosomal turnover rate.
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